* * * * *
EFFECTS OF MORPHINE ON THE FEMALE ORGANS.—In a paper recently read
before the Obstetric Society of St. Petersburg, Passower related the
history of two cases, which confirms the opinion already supported by
the observation of others, that the long continued use of morphine
eventually leads to atrophy of the female generative organs. In both
cases amenorrhœa was present; intra-uterine measurements taken during a
period of two years showed a diminution in the size of its cavity from
5.1 to 1.9 inches.—_Exchange._
_ACTIONS OF DRUGS ON THE INTESTINES._
By W. C. CALDWELL, M.D.,
Professor of Materia Medica, and Director Pharmacological Laboratory,
College of Physicians and Surgeons, Chicago.
_Concluded from page 164._
METHODS OF EXPERIMENT TO DETERMINE WHERE A DRUG ACTS TO PRODUCE
CATHARSIS.
(_D_) _By introducing a rubber balloon, to which is attached a graduated
rubber tube, through a gastric fistula into the small intestine, and
measuring rate of descent and force carrying it onward to anus._
_Technique of the experiment._—Dogs are suited for this. Hess in his
experiments used the animal immediately after making the fistula; Brandl
and Tappeiner waited for the fistula to heal, and used the same dog a
number of times, usually waiting two weeks before using him again, so
that he would completely recover from the previous experiment. The
balloon is introduced into small intestine and then moderately distended
with water through the tube. After it has passed some distance below the
pylorus, the cathartic is injected through the tube, the instrument
being so constructed that the medicine passes into the intestine just
above the balloon; ferrocyanide of potassium is added to the solution so
as to tell by its reaction with chloride of iron whether the cathartic
solution is in the feces. This method causes no shock and is superior to
opening the abdomen to determine peristalsis.
By this method can be learned:
(1) _The location of the peristalsis._ This is done by examining the
graduated tube and noticing how many feet been drawn in. If after the
cathartic has been introduced above the balloon it does not increase the
rate of descent till it reaches the colon, it shows that the drug acts
on the colon instead of the small intestine; aloes is an example of
this. If it increases its descent in the small intestine, it shows that
the drug acts on the small intestine. If the drug greatly increases its
speed in both small and large intestines, then the drug stimulates
peristalsis through the whole length.
(2) _The rate of the peristalsis._ This is learned simply by noticing
how fast the graduated tube is drawn in.
(3) _The time of peristalsis._ When the tube is not being drawn in there
is no peristalsis, at least where the balloon is; when the drug acts on
the small intestine the peristalsis occurs early; and when on the large
intestine, late.
(4) _The force of the peristalsis._ This can be measured by pulley and
bag of shot attached to the graduated tube. Of course it is necessary to
learn first the lifting power of the peristalsis in the same dog without
a cathartic.
(5) _By injecting a solution of the cathartic into a ligatured loop of
intestine in the living animal._ It is better to use a rabbit or dog
that has been starved for several days so that the intestine will be
empty. After several hours remove the loop and measure the amount of
liquid. If it is increased the drug stimulates secretion. It must not be
forgotten that the irritation of the ligature stimulates secretion, so
it is better to have a similar loop for comparison.
(6) _By injecting an equal quantity of water in two similar loops of
intestine in the living animal, and then injecting the cathartic into
one of them._ Use a starved animal. After several hours remove the loops
and measure the quantity of water in each, if the one containing the
cathartic has not diminished as much as the other, then it diminishes
absorption.
We have now learned how to determine when there is increased
peristalsis, and where it is; when there is increased secretion, and
when there is diminished absorption. We have next to try to learn the
exact manner in which these are produced, but this is far more
difficult:
(_a_) Because the nervous mechanism of the intestines is very
complicated, and at present not very much of its physiology is known.
(_b_) Because instead of the nerves with different functions having a
separate course, they are all in the same sheaths, so that one kind of
fibres at a time cannot be cut. The vagus contains motor, inhibitory
motor, sensory, etc., fibres, so that when one is cut all must be cut.
The same is true of the splanchnic.
(_c_) Because if a drug appears in the urine, sweat, or milk, it is no
proof that it acts in the circulation; for it may act locally, then
afterwards be absorbed, but have no action on the intestinal mechanism.
(_d_) Because if a drug cannot be found in the urine, sweat, or milk, it
is not proof that it does not act in the circulation, and then
afterwards be entirely excreted by the intestinal mucous membrane and
pass out with the feces.
[Illustration: FIG. 5.]
(_e_) Because when a drug, given hypodermatically, purges, it is not
proof that the drug acts as a cathartic in the circulation, and that it
does not act locally, for it may be inactive till it is excreted by the
intestinal mucous membrane, and then act locally.
At present I will speak of peristalsis only. Perhaps as good a way as
any to proceed, though unsatisfactory, is, first, to exclude the brain,
and then, second, the abdominal ganglia, and then, third, experiment on
the excised living intestine.
(1) Exclude the cerebral centres by cutting the vagi and splanchnics.
This is shown in the schematic drawing Fig. 5, in which, for simplicity,
one circle represents all the centres in that location. It must not be
forgotten that cutting splanchnics affects the intestinal vessels. It is
evident that after cutting the vagi and splanchnics the cerebral centres
can have no influence on the intestines. After cutting these nerves,
give the cathartic:
(_a_) If it does not act as a cathartic, this shows that it acts upon
the intestines entirely through the cerebral centres, which now have no
influence upon the intestines. This action is probably direct and not
reflex.
(_b_) If it acts as a cathartic equally as efficient as it does when the
nerves are intact, this shows that it does not act as a cathartic
through the cerebral centres. The action is either on some of the
abdominal ganglia, or on the local intestinal mechanism.
[Illustration: FIG. 6.]
(_c_) If it acts as a cathartic, but much weaker than when the nerves
are intact, this shows that it acts both upon the cerebral centres and
also on some part of the remaining mechanism. This action on the
cerebral centers may be direct, or it may be reflex from irritation of
the intestinal mucous membrane. So far as I have read, no experiments
have been made to determine when the action is direct and when reflex.
It seems probable, though, that something might be learned about it in
the following way, which is illustrated by Fig. 6. Select two similar
starved animals; open abdomens of both and expose one carotid artery in
one of them. Inject a solution of the cathartic in the exposed carotid
and an equal solution in the exposed intestinal loop of the other
animal. Place animals in salt solution in tin vat so as to observe
through incision the intestines.
(1) If the drug acts reflexly by irritation of the intestinal mucous
membrane, it will act quicker in the animal in which the drug was
injected into the intestinal canal (see Fig. 6), because it is there to
begin action at once, while in the other it must first be excreted into
the intestinal canal. The intestine can be observed easily in the salt
solution.
(2) If the drug acts directly upon the cerebral centres, it will act
quicker in the animal in which it was injected into carotid artery,
because in the other animal it has to be absorbed and diffused through
the general circulation before it reaches the centre. Clamping the aorta
would make this more accurate were it not that the intestines are so
easily disturbed by changing the circulation.
[Illustration: FIG. 7.]
(3) Exclude the abdominal ganglia. This can be done either by
extirpating the ganglia, or by using a piece of excised living
intestine. (Fig. 7 represents the abdominal ganglia concerned
destroyed.) After extirpating the ganglia, and performing tracheotomy,
and injecting the cathartic into the small or large intestine, place the
animal in a physiological salt solution in tin vat, and observe the
action of the drug. This experiment is not very satisfactory, because
the vessels are greatly dilated.
(_a_) If the drug does not excite peristalsis, this shows that it acts
through the abdominal or cerebral centres. This action may be direct or
reflex.
(_b_) If the drug excites equally as strong peristalsis as are produced
when the ganglia are intact, this shows that its action is not on the
abdominal ganglia but on the intestine.
(_c_) If the drug excites weaker peristalsis, this shows that it acts at
both places. This may be direct or reflex.
If it is decided that the drug acts on some part of the intestine to
cause the peristalsis, two methods may be used to determine what part it
acts upon:
1st Method.—After performing tracheotomy, opening abdomen and destroying
abdominal ganglia, place the animal in a tin vat containing warm
physiological solution. The first thing is to find out:—
(1) Whether the cathartic acts reflexly by the irritation of the mucous
membrane being transmitted to Auerbach’s plexus, and from there to the
muscles, or
(2) Whether it acts upon some structure in the intestinal wall after
being absorbed.
_Demonstration._—If it acts reflexly, it will act quicker when injected
into intestinal canal than when injected into mesenteric artery. If it
does not act reflexly, it will act quicker when injected into the
artery.
Next determine where in the intestinal wall the cathartic acts. The
points are:
1st. Stimulation of the muscle.
2d. Depression of the inhibitory motor ganglia.
3d. Stimulation of Auerbach’s ganglia, and,
4th. Stimulation of the motor fibres.
_Demonstration._—If the drug in large dose causes tetanic spasm of the
intestinal muscles, which is not affected by electrical stimulation of
the inhibitory motor nerves, this shows that the drug acts directly on
the muscles. In this way it can be shown how physostigmine acts.
If the drug in large dose increases peristalsis, and electrical
stimulation of inhibitory motor nerves has no effect upon it, this shows
that the drug paralyzes the inhibitory motor nerves. It can be shown
that morphine acts in this way. In fifteen or twenty minutes after
giving a dog a grain of morphine hypodermatically, it usually has one
movement of the bowels. A small dose of morphine constipates, because it
stimulates the inhibitory motor nerves. If the drug increases
peristalsis and stimulation of the inhibitory motor nerves lessens the
peristalsis, this shows that the drug either stimulates Auerbach’s
ganglia, or the ends of the motor nerves. By the method above described
Jacobi has made some very elaborate experiments with morphine, atropine,
muscarine, and physostigmine.
2d Method.—A piece of excised living intestine is placed in a suitable
apparatus to keep it moist and warm, and artificial circulation is
established by a canula in the artery, connected with two flasks, as
seen in the drawing copied from Brunton (Fig. 8), in one of which is
pure blood and in the other the poisoned blood, arranged so that either
can be turned on at will. The peristalsis is recorded by the lever,
shown in the drawing. In this way Ludwig and Salvioli studied the action
of a number of drugs.
[Illustration: From Brunton.]